The present invention is concerned with pyrimidine derivatives having HIV replication inhibiting properties. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
Compounds structurally related to the present compounds are disclosed in the prior art.
JP-2,052,360, JP-2,308,248. JP-9,080,676 and JP-9,068,784 disclose a number of trisubstituted pyrimidines useful in photographic material. JP-8,199,163 discloses trisubstituted pyrimidines useful in an organic electroluminescent device. JP-2,300,264 and GB-1,477,349 disclose pyrimidinetriamines for their use in the dye industry.
J. Indian Chem. Soc. (1975), 52(8), 774-775 discloses the synthesis of some bis(arylamino)pyrimidines. J. Heterocycl. Chem. (1973), 10(2), 167-171 discloses the condensation of various aminopyrimidines with picryl halides. J. Org. Chem. (1961), 26, 4433-4440 discloses several triaminopyrimidines as intermediates in the synthesis of triazolo[4,5-d]pyrimidines.
WO 91/18887 discloses diaminopyrimidines as gastric acid secretion inhibitors.
Unexpectedly, it has now been found that the compounds of formula (I) effectively inhibit the replication of the Human Immunodeficiency Virus (HIV) and consequently may be useful for the treatment of individuals infected by HIV.
The present invention concerns the use of the compounds of formula 
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
A is CH, CR4 or N,
n is 0, 1, 2, 3 or 4:
Q is hydrogen or xe2x80x94NR1R2;
R1 and R2 are each independently selected from hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl wherein each of the aforementioned C1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C1-6alkyl)amino, aryl and Het; or
R1 and R2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-12alkyl)aminoC1-4alkylidene;
R3 is hydrogen, aryl, C1-6alkylcarbonyl, C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkyl substituted with C1-6alkyloxycarbonyl; and
each R4 independently is hydroxy, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy or C1-6alkyl substituted with cyano or aminocarbonyl;
R5 is hydrogen or C1-4alkyl;
L is C1-10alkyl, C3-10alkenyl, C3-10alkynyl, C3-7cycloalkyl, or C1-10alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four or where possible five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, C1-6alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and C1-6alkylcarbonyl; or
L is xe2x80x94X1xe2x80x94R6 or xe2x80x94X2xe2x80x94Alkxe2x80x94R7 wherein
R6 and R7 each independently are phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy and trihalomethyl; and
X1 and X2 are each independently xe2x80x94NR3xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94;
Alk is C1-4alkanediyl;
aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, nitro and trifluoromethyl;
Het is an aliphatic or aromatic heterocyclic radical, said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy;
for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.
The present invention also relates to a method of treating warm-blooded animals suffering from HIV (Human Immunodeficiency Virus) infection. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or any subgroup thereof, a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
This invention also concerns compounds of formula 
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein L, Q, R3, R4, R5 and A are as defined under formula (I), and
R4xe2x80x2 is halo, C1-6alkyl, cyano, aminocarbonyl, nitro, trihalomethyl, trihalomethyloxy, or
C1-6alkyl substituted with cyano or aminocarbonyl;
nxe2x80x2 is 0, 1, 2 or 3;
with the proviso that Q and L are other than anilino, 2,4,6-trinitro-anilino, 3-methoxy-anilino, 4-methoxy-anilino, 3,4-dimethoxy-anilino, 3-chloro-4-fluoro-anilino, 4-cyano-anilino, 2-(C1-6alkyl)-anilino, 4-(C1-6alkyl)-anilino, 3-chloro-anilino, 4-bromo-anilino, 4-nitro-anilino, and 4-chloro-anilino.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C1-4alkyl as a group or part of a group encompasses the straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl and the like; C1-6alkyl as a group or part of a group encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C1-4alkyl as well as the higher homologues thereof containing 5 or 6 carbon atoms such as, for example pentyl or hexyl; C1-10alkyl as a group or part of a group group encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C1-6alkyl as well as the higher homologues thereof containing 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl or decyl; C1-12alkyl as a group or part of a group encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C1-10alkyl as well as the higher homologues thereof containing 11 or 12 carbon atoms such as, for example, undecyl, dodecyl and the like; C1-4alkylidene as a group or part of a group defines bivalent straight and branched chained hydrocarbons having from 1 to 4 carbon atoms such as, for example, methylene, ethylidene, propylidene, butylidene and the like; C1-4alkanediyl as a group or part of a group encompasses those radicals defined under C1-4alkylidene as well as other bivalent straight and branched chained hydrocarbons having from 1 to 4 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C3-7cycloalkyl as a group or part of a group is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C3-10alkenyl as a group or part of a group defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 10 carbon atoms such as, for example, 2-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl, 2-nonenyl, 2-decenyl and the like, whereby the carbon atom attached to the pyrimidine ring is preferably an aliphatic carbon atom; C3-10alkynyl as a group or part of a group defines straight and branch chained hydrocarbon radicals containing one triple bond and having from 3 to 10 carbon atoms such as, for example, 2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl. 3-methyl-2-butynyl, 3-hexynyl, 3-heptynyl, 2-octynyl, 2-nonynyl, 2-decynyl and the like, whereby the carbon atom attached to the pyrimidine ring is preferably an aliphatic carbon atom.
It is to be understood that the three substituents [L, Q and NR3(optionally substituted phenyl or pyridyl)] on the pyrimidine ring can be on any free position of the pyrimidine ring. Thus, given the following numbering of the pyrimidine ring 
the three substituents may be connected to the pyrimidine ring in three different ways:
2-L, 4-Q, 6-NR3(optionally substituted phenyl or pyridyl); or
4-L, 2-Q, 6-NR3(optionally substituted phenyl or pyridyl); or
6-L, 4-Q, 2-NR3(optionally substituted phenyl or pyridyl).
The positions 4 and 6 are equivalent to one another. For instance, substitution pattern 6-L, 4-Q, 2-NR3(optionally substituted phenyl or pyridyl), which is a preferred substitution pattern, is equivalent to substitution pattern 4-L, 6-Q, 2-NR3(optionally substituted phenyl or pyridyl). Said subgroup of compounds is represented by formula 
An interesting group of compounds are the compounds of formula 
Of particular interest are those compounds of formula (Ixe2x80x2-1) wherein L and Q are other than anilino, 2,4,6-trinitro-anilino, 4-(C1-6alkyl)-anilino, 4-bromo-anilino, 4-nitro-anilino, and 4-chloro-anilino: and of more particular interest are those compounds of formula (Ixe2x80x2-1) wherein R4xe2x80x2 is cyano, aminocarbonyl or C1-6alkyl substituted with cyano or aminocarbonyl.
The addition salts as mentioned herein are meant to comprise the therapeutically active addition salt forms which the compounds of the present invention are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic, and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of the present invention are able to form. Said salts can conveniently be obtained by treating the compounds of the present invention containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts, and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salts also comprises the hydrates and the solvent addition forms which the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates, and the like.
The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Some of the compounds of the present invention may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term xe2x80x9ccompounds of the present inventionxe2x80x9d is meant to include the compounds of formula (I), (I-1), (Ixe2x80x2), (Ixe2x80x2-1) or any subgroup thereof, also the N-oxides, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
The group containing those compounds of the present invention wherein Q is NR1R2, each R4 independently is hydroxy, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, or trihalomethyloxy ; L is C1-10alkyl, C3-10alkenyl, C3-10alkynyl, C3-7cycloalkyl, or C1-10alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl, indolyl, or indolyl substituted with one, two, three, or four substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, and C1-6alkylcarbonyl, phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, and C1-6alkylcarbonyl; or L is xe2x80x94X1xe2x80x94R6 wherein R6 is phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, cyano, nitro, and trifluoromethyl; is of interest.
Also of interest is the group containing those compounds of the present invention wherein Q is NR1R2; each R4 independently is hydroxy, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, or trihalomethyloxy ; L is C1-10alkyl substituted with one or two substituents independently selected from phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy, and C1-6alkylcarbonyl; or L is xe2x80x94X1xe2x80x94R6 wherein R6 is phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, cyano, nitro, and trifluoromethyl; with the proviso that compounds
(a) N2-hydroxy-N2-methyl-N4,N6-diphenyl-2,4,6-pyrimidinetriamine;
(b) N,N,Nxe2x80x2,Nxe2x80x2,Nxe2x80x3,Nxe2x80x3-hexakis(3-methylphenyl)-2,4,6-pyrimidinetriamine;
(c) N4-methyl-N2-(2-methylphenyl)-N4-phenyl-2,4,6-pyrimidinetriamine;
(d) N4-methyl-N2-(2-methylphenyl)-N4-phenyl-6-(phenylmethyl)-2,4-pyrimidine diamine;
(e) N4-(2-methylphenyl)-6-(phenylmethyl)-2,4-pyrimidinediamine;
(f) N,Nxe2x80x2,Nxe2x80x3-tris(4-methoxyphenyl)-2,4,6-pyrimidinetriamine;
(g) N,Nxe2x80x2-bis(4-hexylphenyl )-6-(4-methoxyphenoxy)-2,4-pyrimidinediamine;
(h) N2,N4-bis(4-hexylphenyl)-N6,N6-dimethyl-2,4,6-pyrimidinetriamine:
(i) N,Nxe2x80x2,Nxe2x80x3-tris(4-hexylphenyl)-2,4,6-pyrimidinetriamine;
(j) N2,N2-dimethyl-N4,N6-bis(4-methylphenyl)-2,4,6-pyrimidinetriamine;
(k) N,Nxe2x80x2,Nxe2x80x3-tris(4-methylphenyl)-2,4,6-pyrimidinetriamine;
(l) N,Nxe2x80x2,Nxe2x80x3-triphenyl-2,4,6-pyrimidinetriamine;
(m) N,N,Nxe2x80x2,Nxe2x80x2,Nxe2x80x3,Nxe2x80x3-hexakis(4-ethoxyphenyl)-2,4,6-pyrimidinetriamine;
(n) N4,N6-bis(2-chlorophenyl)-2,4,6-pyrimidinetriamine;
(o) N4,N6-bis(3-chlorophenyl)-2,4,6-pyrimidinetriamine;
(p) N4,N6-bis(2-ethoxyphenyl)-2,4,6-pyrimidinetriamine;
(q) N4,N6-bis(4-ethoxyphenyl)-2,4,6-pyrimidinetriamine;
(r) N4,N6-bis(2-methylphenyl)-2,4,6-pyrimidinetriamine;
(s) N4,N6-bis(4-bromophenyl)-2,4,6-pyrimidinetriamine;
(t) N4,N6-bis(4-methylphenyl)-2,4,6-pyrimidinetriamine;
(u) N2,N4-bis(4-methoxyphenyl)-2,4,6-pyrimidinetriamine;
(v) N2,N4-bis(4-methylphenyl)-2,4,6-pyrimidinetriamine;
(w) N,Nxe2x80x2,Nxe2x80x3-tris(2,4,6-trinitrophenyl)-2,4,6-pyrimidinetriamine;
(x) N4,N6-bis(4-chlorophenyl)-2,4,6-pyrimidinetriamine;
(y) N4,N6-bis(4-methoxyphenyl)-2,4,6-pyrimidinetriamine;
(z) N2,N4,N6-trimethyl-N2,N4,N6-triphenyl pyrimidine-2,4,6-triyltriamine;
(aa) N4,N4-dimethyl-N2,N6-di-p-tolyl-pyrimidine-2,4,6-triyltriamine; and
(bb) N2,N4-diphenyl-pyrimidine-2,4,6-triyltriamine are not included.
Suitably, Q may also be hydrogen in the above two groups of interest.
A special group of compounds are those compounds of formula (I) or (Ixe2x80x2) wherein n is at least 1 and at least one R4 is cyano; preferably, n is 1 and R4 is cyano substituted in the para position relative to the NR3 moiety.
Another special group of compounds contains those compounds of formula (I) or (Ixe2x80x2) which are other than
(c) N4-methyl-N2-(2-methylphenyl)-N4-phenyl-2,4,6-pyrimidinetriamine;
(d) N4-methyl-N2-(2-methylphenyl)-N4-phenyl-6-(phenylmethyl)-2,4-pyrimidinediamine;
(e) N4-(2-methylphenyl)-6-(phenylmethyl)-2,4-pyrimidinediamine; the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof.
An interesting group of compounds are those compounds of the present invention wherein the NR3(substituted phenyl or pyridyl) moiety is in the 4- or 6-position of the pyrimidine ring.
Another interesting group are those compounds of the present invention wherein each R4 independently is hydroxy, halo, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl, or trihalomethyloxy; R6 is phenyl or phenyl substituted with one, two, or three, four, or five substituents each independently selected from halo, C1-6alkyloxy, C1-6alkylcarbonyl, cyano, nitro, and trifluoromethyl; and aryl is phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, C1-6alkyloxy, cyano, nitro, and trifluoromethyl.
Suitably, Q is NR1R2 wherein R1 is hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl; and R2 is hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl; wherein each of the aforementioned C1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C1-6alkyloxy, hydroxyC1-6alkyloxy, carboxyl, C1-6alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or di(C1-6alkyl)amino, aryl and Het: or R1 and R2 taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido, or mono- or di(C1-12alkyl)aminoC1-4alkylidene.
Suitably, L is C1-10alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl and indolyl may be substituted with one, two, three, four, or where possible five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, C1-6alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy, and C1-6alkylcarbonyl; or L is xe2x80x94X1xe2x80x94R6 or xe2x80x94X2xe2x80x94Alkxe2x80x94R7 and when X1 is NR3, then R6 is phenyl substituted with one, two, three, four, or five substituents each independently selected from C1-6alkyloxycarbonyl, formyl, nitro, and trihalomethyloxy.
Suitably, R4 or R4xe2x80x2 is nitro, trihalomethyloxy, or C1-6alkyl substituted with cyano or aminocarbonyl.
Suitably, R6 is phenyl or phenyl substituted with one, two, three, four, or five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy, and trihalomethyl.
Suitably, both Q and R5 are hydrogen.
Suitably, L is C1-10alkyl substituted with one or two substituents independently selected from C3-7cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl, indanyl, and indolyl may be substituted with one, two, three, four, or where possible five substituents each independently selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, C1-6alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and C1-6alkylcarbonyl; or L is xe2x80x94X1xe2x80x94R6 or xe2x80x94X2xe2x80x94Alkxe2x80x94R7; and R5 is hydrogen.
Particular groups of compounds are those groups wherein one or more of the following conditions are met:
(i) n is 0, 1, 2 or 3;
(ii) Q is hydrogen;
(iii) Q is NR1R2 wherein R1 and R2 are each independently selected from hydrogen, hydroxy, C1-12alkyl C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, cyano wherein the aforementioned C1-12alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, cyano, C1-6alkyloxy, hydroxyC1-6alkyloxy, aryl, and Het; or R1 and R2 taken together may form mono- or di(C1-12alkyl)aminoC1-4alkylidene;
(iv) R3 is hydrogen or C1-6alkyl;
(v) R4 is cyano, aminocarbonyl, amino, nitro, hydroxy, halo, C1-6alkyl, or cyanoC1-6alkyl;
(vi) R4 is cyano, aminocarbonyl, halo, C1-6alkyl or cyanoC1-6alkyl;
(vii) R5 is hyrogen or methyl;
(viii) L is C1-10alkyl substituted with phenyl substituted with one or two halogens; or L is xe2x80x94X1xe2x80x94R6 wherein R6 is phenyl substituted with one, two or three substituents selected from C1-6alkyl, trifluoromethyl, trifluoromethoxy, cyano, and halogen, and X1 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94NR3xe2x80x94; or L is xe2x80x94X2xe2x80x94Alkxe2x80x94R7 wherein R7 is phenyl substituted with one, two, or three substituents selected from C1-6alkyl, cyano, and halogen and X2 is NH.
Other particular compounds are those compounds of the present invention wherein L contains phenyl, 2,6-disubstituted-phenyl, 2,4,6-trisubstituted-phenyl, or 2,3,4,5-tetra-substituted-phenyl;
especially, L contains phenyl, 2,4,6-trihalo-phenyl, 2,4,6-triC1-4alkyl-phenyl, 2,3,4,5-tetrahalo-phenyl, 2,4-dihalo-6-C1-4alkyl-phenyl, 2,6-dihalo-4-C1-4alkyl-phenyl, 2,6-dihalo-4-cyano-phenyl, 2,6-dihalo-4-trifluoromethoxy-phenyl, 2,6-dihalo-4-trifluoromethyl-phenyl, 2,6-diC1-4alkyl-4-halo-phenyl, 2,6-diC1-4alkyl-4-cyano-phenyl, 2,6-dihalo-phenyl, or 2,6-diC1-4alkyl-phenyl;
more in particular, L contains phenyl, 2,4,6-trichloro-phenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, 2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, or 4-cyano-2,6-dimethyl-phenyl.
More particular compounds are the compounds of the present invention wherein L is 2,6-dichlorobenzyl, or L is xe2x80x94X1xe2x80x94R6 wherein X1 is xe2x80x94NR3xe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94 and R6 is 2,4,6-trichlorophenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-di bromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, 2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, 4-cyano-2,6-dimethyl-phenyl; or L is xe2x80x94X2xe2x80x94Alkxe2x80x94R7 wherein xe2x80x94X2xe2x80x94Alkxe2x80x94 is xe2x80x94NHxe2x80x94CH2xe2x80x94 and R7 phenyl.
Still other particular compounds are those compounds of formula (I) where R3 is hydrogen, A is CH, n is 1, and R4 is halo, methyl or cyano and is positioned in the 4 position of the phenyl ring.
Preferred compounds are those compounds of the present invention wherein L is 2,6-dichlorobenzyl and the NR3(optionally substituted phenyl or pyridyl) moiety represents p-cyano-anilino and is in the 2 position of the pyrimidine ring.
Other preferred compounds are those compounds of the present invention wherein Q is hydrogen, L is xe2x80x94X1xe2x80x94R6 wherein X1 is xe2x80x94NHxe2x80x94 and R6 is 2,4,6-trimethyl-phenyl or 4-cyano-2,6-dimethylphenyl, the NR3(optionally substituted phenyl or pyridyl) moiety represents p-cyano-anilino and is in the 2 position of the pyrimidine ring.
Still other preferred compounds are those compounds of the present invention wherein L is xe2x80x94X2xe2x80x94Alkxe2x80x94R7 wherein X2 is xe2x80x94NHxe2x80x94, Alk is methylene and R7 is phenyl, 2,6-dichloro-phenyl, 2,4,6-trimethyl-phenyl or 4-cyano-2,6-dimethylphenyl.
More preferred are those compounds of formula (Ixe2x80x2-1) wherein R4xe2x80x2 is halo, cyano, aminocarbonyl, or cyanoC1-6alkyl; n is zero, A is CH, R3 is hydrogen; R5 is hydrogen or methyl; Q is hydrogen or NHR1; and L contains phenyl, 2,4,6-trichloro-phenyl, 2,4,6-trimethyl-phenyl, 2,4-dibromo-3,5-dichloro-phenyl, 2,4-dibromo-6-fluoro-phenyl, 2,4-dichloro-6-methyl-phenyl, 2,6-dibromo-4-isopropyl-phenyl, 2,6-dibromo-4-methyl-phenyl, 2,6-dibromo-4-prop-1-yl-phenyl, 2,6-dichloro-4-cyano-phenyl, 2,6-dichloro-4-trifluoromethoxy-phenyl, 2,6-dichloro-4-trifluoromethyl-phenyl, 2,6-dichloro-phenyl, 2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl, 2,6-dimethyl-phenyl, 2-bromo-4-fluoro-6-methyl-phenyl, 2-bromo-6-chloro-4-fluoro-phenyl, 4-bromo-2,6-dimethyl-phenyl, 4-chloro-2,6-dimethyl-phenyl, or 4-cyano-2,6-dimethyl-phenyl.
Most preferred are
4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile;
6-[(2,6-dichlorophenyl)methyl]-N2-(4-fluorophenyl)-2,4-pyrimidinediamine;
4-[[4-[(2,4-dichlorophenyl)methyl]-6-[(4-hydroxybutyl)amino]-2-pyrimidinyl]amino]-benzonitrile;
4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(3-hydroxypropyl)amino]-2-pyrimidinyl]amino]-benzonitrile;
N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-acetamide;
N-[2-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-butanamide;
4-[[2-amino-6-(2,6-dichlorophenoxy)-4-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2-hydroxy-2-phenylethyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-2-pyrimidinyl]amino]benzontrile;
4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[2-(2-hydroxyethoxy)ethyl]amino]-2-pyrimidinyl]amino]benzontrile monohydrochloride;
4-[[4-[(2,6-dichlorophenyl)methyl]-6-[(2,3-dihydroxypropyl)amino]-2-pyrimidinyl]-amino]benzonitrile;
4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-2-pyrimidinyl]amino]-benzonitrile;
4-[[4-[(2-cyanoethyl)amino]-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]-benzonitrile;
4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[2-(1-pyrrolidinyl)ethyl]amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]-benzonitrile;
N2-(4-bromophenyl)-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2,4-pyrimidinediamine;
4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,6-dichlorophenyl)thio]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[[2,6-dichloro-4-(trifluoromethyl)phenyl]amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile;
4-[[4-[(2,4-dibromo-6-fluorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-5-methyl-2-pyrimidinyl]amino]benzeneacetonitrile;
4-[[4-[methyl(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,4,6-trichlorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,4,6-trimethylphenyl)amino-2-pyrimidinyl]amino]benzonitrile;
4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[2-amino-6-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile;
4-[[4-(2-bromo-4-chloro-6-methylphenoxy)-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
3,5-dichloro-4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]amino]benzonitrile;
4-[[4-[[2,6-dichloro-4-(trifluoromethoxy)phenyl]amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,4-dibromo-3,6-dichlorophenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,6-dibromo-4-propylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide;
4-[[4-[(4-(1,1-dimethylethyl)-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;
4-[[2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile;
4-[[4-[(4-chloro-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]benzonitrile;
4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino-3,5-dimethylbenzonitrile;
4-[[4-[[4-(1,1-dimethylethyl)-2,6-dimethylphenyl]amino]-5-methyl-2-pyrimidinyl]amino]benzonitrile;
4-[[4-((4-bromo-2,6-dimethylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]benzonitrile;
4-[[5-methyl-4-[(2,4,6-trimethylphenyl)thio]-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,6-dibromo-4-propylphenyl)amino]-5-methyl-2-pyrimidinyl]amino]benzonitrile;
4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzamide, N3-oxide;
N2-(4-chlorophenyl)-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine;
4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-5-methyl-2-pyrimidinyl]amino]benzonitrile;
4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethyl benzonitrile;
4-[[4-[(phenylmethyl)amino]-2-pyrimidinyl]amino]benzonitrile;
the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof.
The compounds of formula (I) can be prepared according to art-known procedures.
In particular, compounds of formula (Ixe2x80x2) can generally be prepared by reacting an intermediate of formula (II-A) wherein W1 is a suitable leaving croup such as, for example, a halogen, with an amino derivative of formula (III) optionally in a solvent such as, for example, water, 2-propanol, diethylether, 1-methyl-2-pyrrolidinone and the like, and optionally in the presence of an acid such as, for example, 1 N hydrochloric acid in diethylether. It may be convenient to perform the reaction under a reaction-inert atmosphere such as, for example, oxygen free argon or nitrogen. 
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration, and chromatography.
Analogously to the reaction procedure described above, Hxe2x80x94NR1R2 (VI) can also be reacted with an intermediate of formula (II-B). 
Suitable solvents for the above reaction include, for instance, 2-propanol or 1,4-dioxane.
In case Q is NR1R2 and R2 contains a hydroxy moiety, it may be convenient to perform the above reaction with a protected form of intermediate (VI) whereby the hydroxy moiety bears a suitable protecting group P being, for instance, a benzyl, and subsequently removing the protective group according to art-known methodologies, such as, for example, reacting with BBr3 in dichloromethane under nitrogen atmosphere.
It is also possible to react Hxe2x80x94X1xe2x80x94R6 with an intermediate of formula (II-C) in a suitable solvent such as, for example, 1,4-dioxane, thus obtaining compounds of formula (Ixe2x80x2) wherein L is xe2x80x94X1xe2x80x94R6, said compounds being represented by formula (Ixe2x80x2-c). 
Depending on the nature of X1 a suitable base or acid may be used to improve the reaction rate. For instance, in case X1 is xe2x80x94Oxe2x80x94, sodium hydride may be used as suitable base; or in case X1 is NR3, HCl may be used as a suitable acid.
The compounds of formula (Ixe2x80x2) may further be prepared by converting compounds of formula (Ixe2x80x2) into each other according to art-known group transformation reactions.
For instance, compounds of formula (Ixe2x80x2) whereby Q is NR1R2 and R1 and R2 are taken together to form mono- or di(C1-12alkyl)aminoC1-4alkylidene, said compounds being represented by formula (Ixe2x80x2-a), may be prepared by reacting a compound of formula (Ixe2x80x2) wherein R1 and R2 are hydrogen, with an intermediate of formula (IV) or a functional derivative thereof. 
Also, compounds of formula (Ixe2x80x2) wherein Q is NR1R2 and R1 and R2 are hydrogen may further be reacted with an acyl halide or an alkyl chloroformate in a reaction-inert solvent such as, for example dichloromethane, in the presence of a suitable base, such as, for example, pyridine, to form the corresponding amide, respectively, carbamate derivative.
Some of the compounds of formula (Ixe2x80x2) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds, then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemicalty isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (Ixe2x80x2) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
The above specified reaction procedures for the preparation of compounds of formula (Ixe2x80x2) or subgroups thereof, can also be applied for the preparation of compounds of formula (I).
Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.
Intermediates of formula (II-A) wherein Q is NR1R2, said intermediates being represented by formula (II-A-1), can be prepared by reacting a pyrimidine derivative of formula (V) wherein W2 is a suitable leaving group such as, for example, a halogen, with HNR1R2 (VI) in a reaction inert solvent such as, for example, 1,4-dioxane, 2-propanol, or the like. Different regio-specific isomers may be formed and can be separated from one another using suitable separation techniques such as, for example, chromatography. 
Intermediates of formula (II-B) can be prepared analogously to the preparation of compounds of formula (Ixe2x80x2) starting from intermediates (II-A) and (III). 
A particular subgroup of the intermediates of formula (II-B) is represented by formula 
Particular intermediates of formula (IIxe2x80x2-B) are those wherein W1 is a halogen, more in particular, a chloro atom.
Intermediates of formula (V) whereby Q is NR1R2 and the L is Lxe2x80x2xe2x80x94CH2 and is attached in the 2 position of the pyrimidine ring and W2 is chloro, said intermediates being represented by formula (V-a), can be prepared by reacting an imidamide of formula (VII) with a propanedioic acid ester of formula (VIII) in a solvent such as, for example, ethanol, and in the presence of, for instance, sodium, and subsequently reacting the thus formed intermediate of formula (IX) with a suitable reagent such as, for example, phosphoryl chloride. 
Intermediates of formula (V) whereby Q is NR1R2 and L is Lxe2x80x2xe2x80x94CH2 and is attached in the 4 or 6 position of the pyrimidine ring and W2 is chloro, said intermediates being represented by formula (V-b), can be prepared by reacting an intermediate of formula (X) with urea or a functional derivative thereof, in a solvent such as, for example, ethanol, and in the presence of, for instance, sodium, and subsequently reacting the thus formed intermediate of formula (XI) with a suitable reagent such as, for example, phosphoryl chloride. 
Intermediates of formula (V) wherein Q is NR1R2 and L is Lxe2x80x2xe2x80x94CH2 and is attached anywhere on the pyrimidine ring, said intermediates being represented by formula (V-c), can be prepared by reacting an intermediate of formula (XII-1), for Q is NR1R2 and formula (XII-2) for Q is hydrogen, wherein W2 is a suitbale leaving group such as, for example, a halogen, with an intermediate of formula (XIII) wherein W3 is a suitable leaving group such as, for example, a halogen, according to the procedure of a Grignard reaction. 
Intermediates of formula (V) whereby Q is NR1R2 and L is xe2x80x94Oxe2x80x94R6 or xe2x80x94NHxe2x80x94R6 and is attached in the 4 or 6 position of the pyrimidine ring, said intermediates being represented by formula (V-d), can be prepared by reacting an intermediate of formula (XIV) with an intermediate of formula (XII) wherein W2 is a suitable leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, tetrahydrofuran or 1,4-dioxane, and in the presence of a suitable base such as, for example, potassium hydroxide or diisopropyl ethaneamine, or sodium hydride. 
The intermediates of formula (V-a) to (V-d) can analogously be prepared for the compounds of formula (Ixe2x80x2) wherein Q is hydrogen. To this effect, there is one leaving group W2 less on the pyrimidine ring of the respective starting material.
Compounds of formula (Ixe2x80x2) and some of the intermediates may have one or more stereogenic centers in their structure, present in a R or a S configuration.
The compounds of formula (Ixe2x80x2) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The compounds of the present invention and the intermediates of formula (IIxe2x80x2-B) show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally. Hence, the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HIV infection include thrombocytopaenia. Kaposi""s sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia, and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
The present compounds also show activity against HIV-1 strains that have acquired resistance to art-known non-nucleoside reverse transcriptase inhibitors. They also have little or no binding affinity to human xcex1-1 acid glycoprotein.
Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of the present invention are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.
The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1.
The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions, or suspensions and the like, and segregated multiples thereof.
Those of skill in the treatment of HIV-infection could determine the effective daily amount from the test results presented here. In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four, or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
Also, the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3xe2x80x2-azido-3xe2x80x2-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (3xe2x80x2-thia-2xe2x80x2-3xe2x80x2-dideoxycytidine, 3TC) and the like; non-nucleoside reverse transciptase inhibitors such as suramine, foscarnet-sodium (trisodium phosphono formate), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2xe2x80x2,3 xe2x80x2-e] [1,4]diazepin-6-one), sustiva (efavirenz), tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione; compounds of the xcex1-APA (xcex1-anilino phenyl acetamide) type e.g. xcex1-[(2-nitro-phenyl)amino]-2,6-dichloro-benzene-acetamide and the like; TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g. indinavir, ritanovir, saquinovir and the like, NMDA receptor inhibitors e.g. pentamidine; xcex1-glycosidase inhibitor e.g. castanospermine and the like; Rnase H inhibitor e.g. dextran (dextran sulfate) and the like; or immunomodulating agents, e.g. levamisole, thymopentin and the like.